Cigarette smoking is the major environmental risk factor for the development of chronic obstructive pulmonary disease (COPD), but genetic determinants other than alphal-antitrypsin deficiency likely also influence COPD susceptibility. Genetic association studies using multiple study designs, multiple population samples, and appropriate adjustments for population stratification are essential to identify and replicate key genetic association results. In Project 2, we have selected 100 candidate genes for COPD from several sources, including previously reported genetic associationsto COPD;multiply replicated genetic associations to asthma, and genes identified by animal models of COPD. A panel of 1536 SNPs (LD- tagging SNPs, previously associated SNPs, and non-synonymous SNPs) in these candidate genes will be tested in 400 COPD cases from the National Emphysema Treatment Trial (NETT) and 400 control subjects from the Normative Aging Study (NAS). Based on these COPD case-control analyses, a subset of 20 genes will be selected for more intensive study. SNPs in these 20 genes will be tested for association in families from the Boston Early-Onset COPD Study to COPD (GOLD Stage >2) and to three quantitative COPD- related phenotypes (FEV1f FEV^FVC, and bronchodilator responsiveness). Based on combined p values from the case-control and family-based analyses, significantly associated COPD genes will be identified. A larger number of SNPs per gene (to provide LD-tagging of HapMap SNPs in Caucasian and African populations with r2 >0.95) in the significantly associated COPD genes will be studied in the NETT COPD case and NAS control populations, Boston Early-Onset COPD families, and African-American COPD cases and controls. Positional candidate genes from animal model QTL studies (Project 3) and genes located near significant SNPs in the asthma genome-wide association study (Project 1) will also be included in this final panel of 1536 SNPs. Genes with SNPs that show significant association with COPD only, asthma only, and both asthma and COPD will be identified. The set of COPD susceptibility genes resulting from these association studies will undergo additional exploratory genetic association analysis including phenotypes for emphysema distribution and severity (in COPD NETT cases).